This new R01 application is submitted in response to Funding Opportunity RFA-CA-15-008 ?Research Answers to NCI's Provocative Questions?. The hypothesis to be tested is in response to PQ3. We hypothesize that the benefit afforded by immune surveillance to the individual and populations of cancer patients may depend on the levels of aneuploidy and expression of the Major Histocompatibility Complex (MHC) complex Class II (MHCII) in the tumor. We further predict that a population of individuals defined by tumors with high aneuploidy and low MHCII expression is at higher risk of progression and poor outcome, and unresponsiveness to immunotherapy by regulating the size and composition of intra-tumor immune infiltrates. Within this new paradigm, we also propose to investigate the possible causative mechanism of aneuploidy- induced proteotoxic stress. The study will be a combination of genomic analyses and immunological interrogation in UCSD Moores Cancer Center patients, and will ultimately seek validation in through TCGA data as well as data from immunotherapy trials. We propose four Aims. (1) To validate aneuploidy/MHC II as predictors of progression and clinical outcome. TCGA data will be interrogated to relate an association between aneuploidy and levels of MHCII expression to overall survival. and response in immunotherapy (ICPi) trials. (2) To measure markers of natural immune response in cancer patients grouped according to aneuploidy/MHC II status. We will study the size and clonality of tumor-infiltrating T cells by profiling TCR reactive with TERT, an antigen expressed by cancer cells at every stage of differentiation, as a proxy of the autochthonous anti-cancer response. By comparing tumor-infiltrating T cells to circulating T cells, we expect to determine if (a) tumor the aneuploidy/MHCII signature predicts T cell infiltration, and (b) lower immune T cell infiltration displays high TCR heterogeneity. (3) To determine whether aneuploidy/MHCII status interferes with response to ICPi therapy. We will determine if high aneuploidy/low MHCII expression impairs immune reactivation after ICPi therapy, and use immunoscore from responder and nonresponder patients. (4) To determine whether proteotoxic stress is the mechanism by which aneuploidy interferes with immune response. Because aneuploidy induces proteotoxic stress, the ensuing UPR provides a mechanistic link between cancer cell biology and immune surveillance. In vitro and in vivo experiments using cells with pharmacologically-induced aneuploidy will be used to determine the extent to which UPR cell nonautonomous effects may account for a disruption of local immunity, i.e., number and characteristics of tumor infiltrating myeloid cells. We believe that an analysis at the interface between cancer genomic and immune surveillance may reveal general rules for immune-mediated control of cancer. This may help stratify patients and their clinical trajectory, and predict clinical responses to immunotherapy more accurately. !